Obsessive-compulsive disorder (OCD) and the spectrum of associated conditions, such as trichotillomania (TTM), Tourette's syndrome, and body dysmorphic disorder, affect about 2-4% of the population worldwide. Clinically, OCD-spectrum (OCDS) disorders are characterized by persistent intrusive thoughts (obsessions), repetitive actions (compulsions), and excessive anxiety. Although OCD has been demonstrated to be heritable, the identification of the underlying risk-conferring genetic variation by means of classic genetic association studies has proven to be difficult. Recently, the possibility of a larger contribution of rare genetic variants to the risk of psychiatric disorder has been suggested by several successful studies. I fully expect that a spectrum of risk allele frequencies exists, which includes not only common variation but also a substantial amount of rare genetic variants that contribute to OCD. This proposal is aimed at identifying rare genetic variation in OCD/TTM. Based on the findings in my lab and in others, I have chosen to draw the OCD-spectrum candidate genes from those which are essential in neurite extension and synapse formation and maintenance. I will employ advanced re-sequencing technology to identify sequence variants in this larger set of candidate genes and test for association of rare variants with the OCDS. Identified statistically significant rare variants will be scrutinized for functional changes related to neurite extension and synaptic function using high content screening. Identifying the genetic profile of rare variants found in the OCDS cohort combined with the functional impact that these variants have will provide insight into the etiology of the OCDS. With these approaches a foundation can be laid for the development of a predictive model of the OCDS. PUBLIC HEALTH RELEVANCE: This proposal has special relevance to the public health as it deals with the obsessive-compulsive disorder spectrum, which affects 2-4% of people. As genetic information becomes rapidly integrated into standard of medical care, proposals such as this help to bridge the gap between gene dysfunction in the obsessive-compulsive spectrum and biological and therapeutic relevancy.